KELL BLOOD GROUP SYSTEM

Kell血型由两种蛋白质Kell和XK组成，通过一个二硫键连接。Kell是一种93 kDa的II型膜糖蛋白，XK是一种50.9 kDa的蛋白质，可穿过膜10次。Kell蛋白以多种多态性形式存在，并且其一些抗原具有高度免疫原性，如果输注不匹配的血液，则会引起严重的反应。母亲对Kell抗原的同种免疫也可引起胎儿和新生儿贫血。我们实验室最近的研究表明，Kell是一种激活内皮素的酶，并对内皮素-3有明显的偏好。内皮素是有效的血管收缩剂，也参与发育过程。XK的功能尚不清楚，但其缺失，McLeod表型，与红细胞无红细胞症和迟发性肌肉和神经异常有关。我们的目标是确定Kell/XK复合物的生理功能，并确定Kell抗体引起胎儿和新生儿贫血的细胞机制。我们实验室最近的研究表明，Kell是一种激活内皮素的酶，并对内皮素-3有明显的偏好。内皮素是有效的血管收缩剂，也参与发育过程。XK的功能尚不清楚，但其缺失，McLeod表型，与红细胞棘红细胞增多症和迟发性肌肉和神经异常有关。我们的目标是确定Kell/XK复合物的生理功能，并确定Kell抗体引起胎儿和新生儿贫血的细胞机制。为了实现我们的目标，我们有三个具体目标。1.为了确定Kell的结构域是必要的底物和酶的特异性，并比较野生型Kell的酶的性质，KEL1和KEL6。KEL1和KEL6多态性在非洲血统的人中具有独特的分布，与高加索人相比，并且可能由于选择压力而发展。2.通过研究Kell和XK基因座和小鼠的靶向破坏，确定Kell和XK蛋白的互补作用。3.确定Kell抗体抑制红细胞生成的机制，重点是Kell抗体与红系祖细胞上新生Kell抗原的相互作用。

The Kell blood group is composed of two proteins, Kell and XK, linked by a single disulfide bond. Kell is a 93 kDa type II membrane glycoprotein and XK a 50.9 kDa protein that traverse the membrane ten times. Kell protein exists in many polymorphic forms and some of its antigens are highly immunogenic and can cause severe reactions if mismatched blood is transfused. Maternal alloimmunization to Kell antigens can also cause fetal and neonatal anemia. Recent studies from our laboratory demonstrated that Kell is an enzyme that activates the endothelins and has marked preference for endothelin-3. The endothelins are potent vasoconstrictors and are also involved in developmental processes. The function of XK is not known but its absence, the McLeod phenotype, is associated with red cell acenthocytosis and late onset forms of muscular and neurological abnormalities. Our objectives are to define the define the physiological functions of the Kell/XK complex and to determine the cellular mechanisms by which antibodies to kell elicit fetal and neonatal anemia. Recent studies from our laboratory demonstrated that Kell is an enzyme that activates the endothelins and has marked preference for endothelin-3. The endothelins are potent vasoconstrictors and are also involved in developmental processes. The function of XK is not known but its absence, the McLeod phenotype, is associated with red cell acanthocytosis and late onset forms of muscular and neurological abnormalities. Our objectives are to define the physiological functions of the Kell/XK complex and to determine the cellular mechanisms by which antibodies to Kell elicit fetal and neonatal anemia. To achieve our objectives we have three specific aims. 1. To identify the domains of Kell that are necessary for substrate and enzymatic specificity and to compare the enzymatic properties of wild-type Kell to those of KEL1 and KEL6. The KEL1 and KEL6 polymorphisms have distinctive distributions in persons of African heritage, as compared to Caucasians, and may have developed due to selective pressures. 2. To determine the complementary roles of Kell and XK proteins, by studying targeted disruption of the Kell and XK loci and mice. 3. To determine the mechanisms by which antibodies to Kell suppress erythropoiesis, with emphasis on the interactions of Kell antibodies with nascent Kell antigens that occur on erythroid progenitor cells.